Parkinson Flashcards
Parkinson’s
Progressive nervous system disease Starts gradually Movement disorder ◦ Bradykinesia ◦ Muscle rigidity ◦ Resting tremors ◦ Postural instability Pathology ◦ Extensive deterioration of neurons within basal ganglia of the brain ◦ Dopamine loss ◦ Increased cholinergic activity
Therapeutic goals
◦ Ideal treatment that reverses neuronal degeneration or prevents further
degeneration does not exist
◦ The goal is to improve the patient’s ability to carry out the activities of daily life
◦ Drug selection and dosages are determined by the extent to which PD interferes
with work, dressing, eating, bathing, and other activities of daily living
Therapeutic Drug Class Alternatives
Dopaminergics Dopamine Agonists MAO B inhibitors Glutamate antagonist (amantadine) Anticholinergics Catechol‐O‐Methyltransferase
Dopaminergics - Options
◦ Levodopa (Dopar, Larodopa)
◦ Levodapa‐carbidopa(Sinemet, Sinemet DR, Madopar)
◦ Duodopa (continuous to small intestine)
Dopaminergics clinical indications
◦ Most effective for tremors and rigidity
◦ Also used: postencephalitic and PD associated with cerebral ateriosclerosis
Levadopa Pharmacokinetics and
Pharmacodynamics - Conversion
Conversion of levodopa to dopamine
◦ Restores normal balance between excitation and inhibition of neurons
◦ Carbifdopa enhances concentration of levodopa to reach brain
Absorption in gut, hampered by food
Biotransformed in liver
Short ½ life, requires frequent dosing
Renally eliminated, breast milk also.
Levadopa SE
◦ N&V most common
◦ Other: dry mouth, difficulty swallowing, worsening hand tremors, numbness, syncope, sudden sleep
Levadopa Long Term Therapy
◦ Dyskinesia, on‐off phenomenon, psychiatric manifestations, cardiac arrhythmia
Levadopa Contraindications
◦ Concurrent MAOIs, uncontrolled HTN, narrow angle glaucoma, malignant melanoma
◦ CVD, Renal, liver disease, PUD, asthma/COPD, adrenergic therapy, Pregnance Cat D, BF, children < 12
Levadopa Prescription and Monitoring
Frequency of dosing patient dependent
◦ 75mg carbidopa needed to achieve full decarboxylation
Target dose
◦ Smallest dosage necessary to control symptoms and decrease disability
Monitoring
◦ Periodic CBC, LFTs, renal studies
May interfere with urine glucose and ketone tests
Dopamine Agonists - Options
◦ Bromocriptine (Parlodel) ◦ Pergolide (Permax) ◦ Rotigotine (patch) ◦ Apomorphine (IV/IM) Ropinirole (Requip CR) ◦ Pramipexole (Mirapex)
Dopamine Agonists - Clinical Indications
◦ Idiopathic and encephalic PD, restless legs
◦ Adjunct to levodopa
◦ Cannot be discontinued abruptly
◦ Require 3x a day dosing
Dopamine Agonists - PK/PD
◦ Pramipexole no hepatic metabolism
Dopamine Agonists SE
◦ Orthostatic hypotension, GI disturbance, less dyskinesia, drowsiness, insomnia
◦ Dyspnea, angina, arrhythmias, orthostosis possible (esp. in hot environs), compulsive behaviors
Dopamine Agonists - Interacions
Pergolide
Monamine Oxidase B Inhibitors - Options
◦ Selegiline (Eldepryl)
◦ Rasegeline (Agilect, Zelipar)
◦ Safinamide
Monamine Oxidase B Inhibitors - Clinical Indications
◦ Adjunct to Levodopa
◦ Most effective early stages, early onset
Monamine Oxidase B Inhibitors - MOA
◦ Selegiline:
◦ blocks MAO‐B; neuroprotective properties?
◦ May be monotherapy; dose twice daily
◦ Amphetamine metabolites
◦ Rasegiline:
◦ Prolongs survival of dopamine neurons; neuroprotective properties?
Monamine Oxidase B Inhibitors SE
Nause, dry mouth, constipation, confusion, hallucinations, lightheadedness, drug/food interactions
Monamine Oxidase B Inhibitors - Seleginie
◦ Side effects similar to levodopa
◦ Cautious use of doses of 10mg/d
◦ Caution: PUD, arrhythmia, TDK, psychosis
Monamine Oxidase B Inhibitors - Rasegiline
◦ SE similar to levodopa in combo
◦ May exacerbate dyskinesia
◦ Interactions TCAs. Selegiline: CNS toxicity, death
Glutamate Antagonist - Clinical indications
◦ Clinical Indications ◦ Limited efficacy, rarely prescribed initially, adjunct ◦ Effects short‐lived and mild ◦ Has stimulatory effect for some ◦ Especially useful if tremors prominent
Glutamate Antagonist - MOA
◦ Reduces drug‐induced dyskinesias without worsening other symptoms
Glutamate Antagonist - SE
SE: peripheral edema, skin mottling, confusion; toxic SE more common older adults
Anticholinergics - Options
◦ Trihexyphenidyl (Broflex, Artane, Agitane)
◦ Benztropine (Cogentin)antipsychotic drug‐induced PD)
◦ Orphenadrine (Disipal)
◦ Procyclidine (Kemadrin, Arpicolin)
Anticholinergics - Clinical Inidcations
◦ Early in early onset, tremor but little rigidity or bradykinesia, drooling, EPS
◦ Not in older adults or those with dementia; BPH, Closed angle glaucoma
Specifics - MOA
◦ Inhibit acetylcholine at muscarinic receptors
◦ Restore cholinergic‐dopaminergic balance
Specifics - SE
◦ Worse in older adults
◦ Dry mouth, constipation, urinary retention, tachycardia,palpitations, impaired sweating
Specifics - Interactions
◦ Antipsychotics, antihistamines, antidepressants
Catechol‐O‐Methyltransferase (COMT) - Options
◦ Entacopone (Comtan)
◦ Tolcapone (Tasmar)+
Catechol‐O‐Methyltransferase (COMT) - Clinical Indications
◦ Adjunct to levodopa
◦ Ineffective when given alone
Catechol‐O‐Methyltransferase (COMT) - MOA
◦ Higher sustained serum levels of dopamine
Catechol‐O‐Methyltransferase (COMT) - SE
◦ Due to increased dopaminergic stimulation
◦ Tolcapone: dsykinesia, hallucinations, confusion, N, orthostatic hypotension. Entacopone: N, dyskinesia
Therapeutic Goals
Ideal treatment that reverses neuronal degeneration or
prevents further degeneration does not exist
The goal is to improve the patient’s ability to carry out
the activities of daily life
Drug selection and dosages are determined by the
extent to which PD interferes with work, dressing,
eating, bathing, and other activities of daily living
Management Strategies
Consider
◦ Patient age
◦ Signs and symptoms
◦ Stage of Disease
◦ Degree of functional disability
◦ Level of physical activity and productivity
◦ Shared decision‐making
◦ The effect of disease on the dominant hand
◦ The degree to which the disease interferes with work, activities of daily living, or social and leisure function
◦ The presence of significant bradykinesia or gait disturbance
◦ Patient values and preferences regarding the use of medications
MAO‐B Inhibitors - Patients at any age
◦ Patients at any age with very early PD and minimal signs and symptoms who are looking for a small
amount of benefit
Glutamate Antagonists (Amantadine) - fast facts
◦ Patients with PD and mild symptoms, particularly when tremor is prominent
◦ Well‐tolerated in younger patients
Anticholinergics fast facts
◦ Patients with PD who are ≤65 years of age and have disturbing tremor but do not have significant
bradykinesia or gait disturbance
◦ Patients with more advanced disease who have persistent tremor despite treatment with levodopa or
DA
Initial Treatment Progressive Disease ≤
65 Years Mild to Moderate
Levodopa or levodopa‐carbidopa first line for many
◦ Tailor to individual
Progressive disease usually requires more than monotherapy with dopamine agonist after a few
years
Debate over the potential neuroprotective vs. neurotoxic effects of levodopa remains
unresolved
Initial Treatment Progressive Disease >
65 Years Mild to Moderate
Levodopa recommended for older adult
◦ DAs are not well tolerated in older adults and those with cognitive dysfunction
◦ Levodopa is more effective for improving motor function and quality of life
Debate over the potential neuroprotective vs. neurotoxic effects of levodopa remains
unresolved
Moderate to Severe Disease Any Age
Levodopa preferred
◦ L‐dopa main precursor of dopamine synthesis
Most effective drug for symptomatic treatment of PD
Superior effects on:
◦ Motor function
◦ Activities of daily living
◦ Quality of life
Titration and Maintenance
Titrate up slowly
Maintain levodopa at lowest effective dose
Add adjunct therapy based on age, symptoms
Monitor for side effects
Lower dose of levodopa if side effects increasing
Monitor for drug interactions
Monitor renal and liver status
On‐Off Phenomenon
A switch between mobility and immobility in levodopa‐treated patients
Occurs as an end of‐dose or “wearing off” worsening of motor function
Or, much less commonly, as sudden and unpredictable motor fluctuations
Non‐Motor Symptoms
90% of patients develop nonmotor symptoms (e.g., autonomic disturbances, depression, dementia, psychosis) Autonomic symptoms ◦ Constipation, urinary incontinence, drooling, orthostatic hypotension, and cold intolerance Sleep disturbance ◦ Excessive daytime sleepiness ◦ Periodic limb movements of sleep ◦ Insomnia
Parkinsonism‐Hyperpyrexia Syndrome
Rare occurrence
Sudden withdrawal or dose reduction of antiparkinson medication
Or when switching from 1 drug to another
◦ Most common drugs: Levodopa, dopamine agonist, rare amantadine
Management
◦ Replace antiparkinson medications
◦ Formuations: oral, NG, IV, infusion, transdermal
Severe symptoms: admit
